Pharmacological and Pharmacokinetic Studies of a K_Ca2.2 Positive Allosteric Modulator

Author

Mohammad Asikur Rahman, Chapman UniversityFollow

Date of Award

Summer 8-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Dr. Miao Zhang

Second Advisor

Dr. Sun Yang

Third Advisor

Dr. Keykavous Parang

Fourth Advisor

Dr. Meng Cui

Abstract

Small-conductance Ca²⁺-activated potassium channels (K_Ca2.x) family is widely expressed in neurons, the heart, and endothelial cells. K_Ca2.x channels are named small conductance Ca²⁺-activated potassium channels due to their comparatively low single-channel conductance and are activated solely by rises in intracellular Ca²⁺. The family has three subtypes: K_Ca2.1, K_Ca2.2, and K_Ca2.3, encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. K_Ca2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. Small-conductance Ca²⁺-activated potassium channels subtype 2 (K_Ca2.2, also called SK2) is a promising drug target for spinocerebellar ataxias (SCAs), genetic disorders with no available treatment. Heterozygous genetic mutations of K_Ca2.2 channels have been associated with autosomal dominant neurodevelopmental disorders, including cerebellar ataxia and tremor in humans and rodents. The structure-function studies of the rat K_Ca2.2 channel using seven pathogenic mutations (I289N, I360M, Y362C, G363S, I389V, L174P, and L433P) associated with these disorders were performed to investigate the insight of these disorders related to K_Ca2.2. The dominant mutations negatively suppressed and completely abolished the activity of the co-expressed K_Ca2.2_WT channel, suggesting that these mutations may be causative in neurodevelopmental disorders. Additionally, the co-expression of the K_Ca2.2_I289N and the K_Ca2.2_WT channels reduced the apparent Ca²⁺ sensitivity compared with the K_Ca2.2_WT channel rescued by a K_Ca2.2 positive modulator. A positive allosteric modulator of K_Ca2.2/K_Ca2.3 channels (compound 2q) has been developed, and a method for quantitating it in mouse plasma has been validated using FDA guidelines. The developed assay is suitable for preclinical pharmacokinetic-pharmacodynamic studies of 2q as a potential drug candidate for ataxias.

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Recommended Citation

Rahman, M.A. Pharmacological and Pharmacokinetic Studies of a K_Ca2.2 Positive Allosteric Modulator. [dissertation]. Irvine, CA: Chapman University; 2023. https://doi.org/10.36837/chapman.000498